Wound management has been one of the most challenging tasks for medical professionals.
In the past, many wound healing agents and methods for local wound management have been developed. Some of the traditional wound healing agents, though now less widely used, are still beneficial in certain clinical settings for wound treatment. Such wound healing methods include liquid or semi-solid formulations of povidone-iodine, silver, and polyhexamethlene biguanide used topically or incorporated into dressings to promote wound healing. Additional traditional approaches to wound healing include physiological saline solution, silver nitrate ointment, and dressings including gauze, cotton, wool, and synthetic or natural bandage.
Most of the traditional wound healing methods have been replaced by modern wound management techniques and increasingly more studies have been dedicated to develop methods and agents to promote wound healing.
Topical application of biologically active compounds has been proven to be an effective method for promoting wound healing. These active compounds include growth factors, mitogens, and hormones. However, such applications are limited in that it is difficult to regulate the dosage of the active compounds and the compounds rapidly degrade. For example, U.S. Patent Application Publication No. 20060188486 to Carpenter et al. discloses wound healing polymer compositions that release a wound healing agent at a controlled rate. The wound healing agents disclosed include proteinaceous growth factors, vascular endothelial growth factors, anti-proliferant agent, antimicrobials, anti-inflammatory agents, tissue grafts and wound healing cells.
One of the most popular techniques among modern methods for promoting wound healing is the application of monomer and polymer tissue adhesives. Included among these adhesives are the 1,1-disubstituted ethylene monomers and polymers, such as the alpha-cyanoacrylates. Since the discovery of the adhesive properties of such monomers and polymers, they have found wide use due to the speed with which they cure, the strength of the resulting bond formed, and their relative ease of use. These characteristics have made alpha-cyanoacrylate adhesives the primary choice for numerous applications even outside the medical arena, including industrial and home use in bonding plastics, rubbers, glass, metals, and wood.
Tissue adhesives have been investigated extensively as the healing agent for topical wounds. Compared to suture and other wound closure agents, cyanoacrylate adhesives demonstrate similar cosmetic results, but more importantly, improve the rate of wound closure (Quinn et al. JAMA, 277, 1527-30, 1997). It has also been found that cyanoacrylate tissue adhesives can be the preferred method in terms of cosmetic appearance for the cutaneous closure of facial lacerations (Simon et al. J. Emerg. Med. 16, 185, 1998). Besides faster wound closure and better cosmesis, advantages of cyanoacrylate adhesives over suture or staples also include lower infection rates. And, the recently FDA approved and commercially available SurgiSeal® topical skin adhesive, which is a 2-octylcyanoacrylate, has shown a desirable water vapor transmission rate (WVTR) which could be beneficial to wound healing. (SurgiSeal® topical skin adhesive is manufactured by Adhezion Biomedical, LLC, Wyomissing, Pa.)
Although the source for this characteristic is not understood it has been observed that cyanoacrylate compositions inherently possess some antimicrobial activity. In particular, cyanoacrylate compositions themselves are believed to prevent the growth of some types of microorganisms within the compositions. But because this property is limited, in order to further enhance wound healing using cyanoacrylate adhesives, different wound healing agents have been incorporated into cyanoacrylate tissue adhesives. For example, U.S. Patent Application Publication No. 20050042266 to Narang and U.S. Pat. Nos. 5,684042, 5,762,919, 5,811,091 and 5,783,177 to Greff et al. disclose that an effective amount of antimicrobial agents can be incorporated into cyanoacrylate adhesive compositions to promote wound healing.
U.S. Pat. No. 6,214,332 to Askill et al. discloses antimicrobial cyanoacrylate ester compositions which may further include medicaments, such as growth factors such as epidermal growth factor, platelet derived growth factor, transforming growth factors, keratinocyte growth factor and fibroblast growth factor. However, as a general matter, it has been a challenging task to incorporate medicaments into cyanoacrylate adhesives. Most medicaments are not soluble in cyanoacrylates. Additionally, many if not most medicaments negatively affect the polymerization rate of the monomer composition, either by acting as inhibitors or as initiators. Thus, the cyanoacrylate could be prevented from curing (polymerizing) or induced to prematurely polymerize resulting in an undesirable reduction or destruction of the shelf-life stability of the cyanoacrylate. Additionally, incorporation of medicaments could also affect the viscosity of the composition and the resulting performance of the cyanoacrylate in terms of cure time and bonding strength. In addition, medicaments based on protein could be inactivated due to the binding of protein to cyanoacrylate, as U.S. Pat. No. 5,684,042 to Greff et al. discloses. Therefore, better methods and compositions are still needed with regard to promoting wound healing.
Another wound healing accelerator is phenytoin. Phenytoin refers to diphenylhydantoin or 5,5-diphenylimidazolidine-2,4-dione, which originally was introduced into therapy in 1937 as an effective anticonvulsant in the treatment of epileptic patients. It has been noted that a common side effect of phenytoin treatment for seizures is the development of fibrous overgrowth of gingival (gums). It is believed that this occurs by the phenytoin stimulating responsive sub-population of fibroblasts to synthesize the increased amount of collagen. The great potential of phenytoin in wound healing is thus derived from the obvious stimulatory effect of phenytoin on connective tissue.
U.S. Patent Application Publication No. 20090022779 to Kelly et al. discloses gel-based phenytoin formulations suitable for topical application to wound sites. The disclosed compositions contain phenytoin dissolved in an aqueous component of gel and solid powder which entraps the phenytoin. The gelling agent can be selected from alginic acid, chitosan and its derivatives, and a carbomer.
In vivo and clinical studies have demonstrated that topical phenytoin provides advantages as a wound healing agent. A controlled clinical trial, using phenytoin by applying it to periodontal patients with surgical wounds, reported that phenytoin accelerated wound healing and reduced inflammation and pain (Shapiro, Exp. Med. Surg. 16, 41-53, 1958). Furthermore, a large number of clinical studies concluded that phenytoin therapy has a beneficial effect on healing of various wound types including surgical wounds, burns, pressure ulcers, traumatic wounds, decubitus ulcers, venous stasis ulcers, and diabetic ulcers, many of which are difficult and chronic wounds (Naeini et al. J. Anim. Vet. Adv. 12, 1537-1545, 2008; Talas et al. Biochem. Pharmacol. 57, 1085-1094, 1999; Bhatia et al., Dermatol. Online J. 10, 5, 2004; Scheinfeld Dermatol. Online J. 9, 6, 2003). It is believed that phenytoin has a stimulatory effect on tissue growth by improving granulation tissue formation which is beneficial to wound healing.
Besides enhancing wound healing, phenytoin has an antimicrobial property and has been shown to decrease the bacterial load of wounds as proved by a number of clinical studies (Pendse et al. Int. J. Dermatol. 32, 214-7, 1993). In addition, topical phenytoin therapy can relieve local pain when applied onto the wound site due to its membrane-stabilizing property thereby providing rapid relief for patient's comfort. Additionally, phenytoin can reduce inflammation and wound transudation. And, as a wound healing agent, phenytoin could possibly accelerate nerve regeneration. Other advantages are that phenytoin is safe to use, cost effective and readily available as opposed to expensive alternatives such as a mixture of synthetic growth factors.
Considering the established efficacy of phenytoin in promoting wound healing, there is a clear need for methods through which the effective wound healing property of phenytoin may be provided in a convenient, stable, efficacious and reproducible manner to local wounds.
A need also exists for improved adhesive compositions, especially for medical uses, that contain medicaments, but where the performance of the adhesive composition is not compromised.